title: Regulation of the transcriptional coactivator FHL2 licenses activation of the androgen receptor in castrate-resistant prostate cancer.
abstract: It is now clear that progression from localized prostate cancer to incurable castrate-resistant prostate cancer (CRPC) is driven by continued androgen receptor (AR), signaling independently of androgen. Thus, there remains a strong rationale to suppress AR activity as the single most important therapeutic goal in CRPC treatment. Although the expression of ligand-independent AR splice variants confers resistance to AR-targeted therapy and progression to lethal castrate-resistant cancer, the molecular regulators of AR activity in CRPC remain unclear, in particular those pathways that potentiate the function of mutant AR in CRPC. Here, we identify FHL2 as a novel coactivator of ligand-independent AR variants that are important in CRPC. We show that the nuclear localization of FHL2 and coactivation of the AR is driven by calpain cleavage of the cytoskeletal protein filamin, a pathway that shows differential activation in prostate epithelial versus prostate cancer cell lines. We further identify a novel FHL2-AR-filamin transcription complex, revealing how deregulation of this axis promotes the constitutive, ligand-independent activation of AR variants, which are present in CRPC. Critically, the calpain-cleaved filamin fragment and FHL2 are present in the nucleus only in CRPC and not benign prostate tissue or localized prostate cancer. Thus, our work provides mechanistic insight into the enhanced AR activation, most notably of the recently identified AR variants, including AR-V7 that drives CRPC progression. Furthermore, our results identify the first disease-specific mechanism for deregulation of FHL2 nuclear localization during cancer progression. These results offer general import beyond prostate cancer, given that nuclear FHL2 is characteristic of other human cancers where oncogenic transcription factors that drive disease are activated like the AR in prostate cancer.
authors.affiliation: Department of Biochemistry and Molecular Biology and Immunology, Monash University, Clayton Victoria, Australia.
authors.forename: Meagan J
authors.initials: MJ
authors.lastname: McGrath
authors.forename: Lauren C
authors.initials: LC
authors.lastname: Binge
authors.forename: Absorn
authors.initials: A
authors.lastname: Sriratana
authors.forename: Hong
authors.initials: H
authors.lastname: Wang
authors.forename: Paul A
authors.initials: PA
authors.lastname: Robinson
authors.forename: David
authors.initials: D
authors.lastname: Pook
authors.forename: Clare G
authors.initials: CG
authors.lastname: Fedele
authors.forename: Susan
authors.initials: S
authors.lastname: Brown
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Dyson
authors.forename: Denny L
authors.initials: DL
authors.lastname: Cottle
authors.forename: Belinda S
authors.initials: BS
authors.lastname: Cowling
authors.forename: Birunthi
authors.initials: B
authors.lastname: Niranjan
authors.forename: Gail P
authors.initials: GP
authors.lastname: Risbridger
authors.forename: Christina A
authors.initials: CA
authors.lastname: Mitchell
mesh_terms: D000818:Animals; D019556:COS Cells; D002154:Calpain / Q000378:metabolism; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism; D002522:Chlorocebus aethiops; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D064448:Filamins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D060850:LIM-Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism*; D008024:Ligands; D008297:Male; D009124:Muscle Proteins / Q000235:genetics* / Q000378:metabolism*; D064129:Prostatic Neoplasms, Castration-Resistant / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D011944:Receptors, Androgen / Q000235:genetics* / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism*; D015533:Transcriptional Activation
chemical_list: C410798:AR protein, human; C105987:FHL2 protein, human; D064448:Filamins; D060850:LIM-Homeodomain Proteins; D008024:Ligands; D009124:Muscle Proteins; D011944:Receptors, Androgen; D014157:Transcription Factors; D002154:Calpain